Translational Research

Advancing Translational Research through Institutional
Resources

George Demetri, MD

In recent years, Dana-Farber has invested in initiatives that
provide the organizational framework and resources needed to
support outstanding translational research. "The overall strategy
behind this considerable institutional support is to facilitate
productive relationships, internally and externally, that lead to
the highest-caliber clinical trials," says George Demetri, MD, of the Department of Medical Oncology
and director of the Ludwig Center for Cancer Research at
Dana-Farber. "Our aim is to decrease drug development time from
twenty years to five by making these connections work effectively,
and ultimately to ensure that the best science ideas from the lab
are converted quickly to the clinic."

The Ludwig Center for Cancer Research at Dana-Farber

The first of only six of its kind in the United States, the
Ludwig Center at Dana-Farber represents an expansion of the
philanthropic vision of American business magnate Daniel K. Ludwig,
who bequeathed his fortune to cancer research. Under the direction
of Demetri, and supported by an endowment in perpetuity, this
academic research center helps to translate scientific discoveries
from the laboratory into the clinic as rapidly as possible. This is
achieved by fostering collaborations among a multidisciplinary
group of investigators and facilitating access to new therapies and
technologies for preclinical and early clinical research.

Among other achievements, the Ludwig Center has been
instrumental in developing novel inhibitors for the treatment of
gastrointestinal stromal tumor (GIST). Approximately 90 percent of
patients benefit from first- and second-line treatment with
tyrosine kinase inhibitors (TKIs), such as imatinib (Gleevec) or
sunitinib (Sutent), which block the activated oncoproteins KIT and
PDGFRA; however, resistance to TKIs evolves when tumors acquire
secondary mutations in the target kinase. Demetri and the team at
Dana-Farber, in collaboration with colleagues at Brigham and
Women's Hospital, sought to inhibit these oncoproteins by targeting
HSP90, a molecular chaperone that escorts "client" proteins and
ensures their proper folding, localization, stability, and
degradation. Since HSP90 appears to protect the mutant KIT
oncoproteins from normal degradation, investigators reasoned that
HSP90 might be a good therapeutic target in GIST and other cancers.
A preclinical study validated HSP90 as a target and found that
inhibition of the molecule dramatically inactivated KIT
oncoproteins in imatinib-resistant GIST cell lines. Later, in
collaboration with Infinity Pharmaceuticals, Demetri and Andrew Wagner, MD, PhD, also of the Department of Medical
Oncology, and colleagues conducted the first Phase I clinical trial
of an HSP90 inhibitor specifically targeting patients with
TKI-resistant GIST and other sarcomas. The inhibitor was generally
well tolerated and showed evidence of efficacy. This trial led to
an international Phase III study in GIST, currently underway, a
Phase II trial in lung cancer, and a Phase I study in breast
cancer.

The initial focus of the Center - developing molecularly
targeted therapies for GIST and other sarcomas - has since expanded
to encompass therapeutic initiatives in melanomas and lung cancers.
"Our center has a uniquely dedicated focus on translational science
and clinical opportunities," says Demetri. "The driving force,
design, and academic control of clinical trials rests firmly in the
hands of Dana-Farber. The Ludwig endowment gives us the certainty
of continuity, long-term vision, and commitment to do this
work."

Imaging in Translational Research

Andrew Kung, MD, PhD

"Imaging technology is a powerful tool in translational
research," says Annick Van den Abbeele, MD, chair of the Department
of Imaging and director of Dana- Farber's Center for Biomedical Imaging in Oncology, or CBIO.
"Integrating our preclinical and clinical imaging research
activities in CBIO will help us evaluate promising new drugs more
efficiently and translate them more rapidly into clinical trials
and practice." A critical component of CBIO is the Lurie Family
Imaging Center, directed by Andrew Kung, MD, PhD, of Pediatric Oncology. The
Center offers state-of-the-art technologies, techniques, and
expertise for conducting small animal experiments. In the facility,
all imaging equipment is located inside the animal housing barrier.
Miniaturized versions of X-ray, CT, PET, SPECT, MRI, and ultrasound
equipment are available, as well as a full range of clinically
relevant radiotracers. Optical imaging provides an additional
research tool for studying molecular targets in living animals.
"These imaging modalities will help investigators understand not
only whether a drug impacts tumor growth, but also whether a drug
modulates its target in vivo," explains Kung. "Imaging is
non-invasive and nonlethal, so it gives us the ability to conduct
longitudinal studies using smaller numbers of mice to obtain
significant results in a matter of days instead of weeks."

Clinical Research Institute

As part of a strategic effort to enhance the quality and impact
of its clinical trials, Dana-Farber recently founded the Clinical
Research Institute (CRI) under the direction of Philip Kantoff, MD, chief clinical research officer. An
educational program, directed by Harold Burstein, MD, PhD, of Medical Oncology, offers an
intensive two-month training program between the first and second
year of fellowship, followed by several hours of coursework per
week. Classes and hands-on workshops focus on how to write and
conduct clinical protocols. Over time, says Kantoff, CRI will
provide training and credentialing for all Dana-Farber clinical
investigators.

In addition, CRI offers consultative services to enhance the
scientific design of investigator-initiated trials. "Before the
protocol is written, the investigator presents the study concept
before a multidisciplinary team of experts, who give their feedback
and advice," explains Kantoff. CRI's research navigator then
facilitates the execution of clinical trials by linking
investigators with services needed for the trial.

"The intent is to elevate the quality and efficiency of clinical
research at Dana-Farber," says Kantoff. "Ultimately, we hope to
create a new generation of clinical trials that will guide us
toward personalized cancer medicine, an area where we expect to
play a leading role." Many of the novel trials emerging from the
efforts of CRI will be conducted in the Early Drug Development
Center (EDDC), directed by Geoffrey Shapiro, MD, PhD. "CRI and EDDC
represent two cornerstones of the larger clinical trials
infrastructure we have built at Dana-Farber to improve outcomes for
cancer patients," says Kantoff.